Parathyroid hormone (PTH) binds to the PTH1 receptor (PTH1R), which is a G protein-coupled receptor (GPCR), to activate the G protein, and then causes activation of at least one signaling cascade such as the cyclic AMP (cAMP)/protein kinase A cascade. PTH is known as a hormone that acts on target cells in the kidney and bone to regulate calcium (Ca) and phosphorus (Pi) homeostasis (Non-Patent Document 1). Serum Ca concentration level is maintained by PTH mainly through direct or indirect actions on the gastrointestinal tract, bone, and kidney. PTH promotes resorption of Ca from the renal tubules and thereby suppresses excretion of Ca in the body to the outside. It also increases the synthesis of an enzyme that converts vitamin D to active vitamin D in the kidney, and thereby contributes to the facilitation of active vitamin D-mediated Ca absorption from the gastrointestinal tract. Furthermore, PTH enhances the differentiation of osteoclasts indirectly via osteoblasts and promote Ca release from the bone. These actions of PTH are thought to occur mainly via the cyclic adenosine 3′,5′-monophosphate (cAMP) elevation and/or phospholipase C (PLC) activation that occurs when PTH binds to the PTH1R.
In humans, PTH preparations [PTH (1-34) and PTH (1-84)] have a powerful osteogenic effect, and induce significant increases in bone mineral density (BMD) and bone strength. Currently, most of the osteoporosis drugs available for humans are inhibitors of bone resorption, and the only type of osteogenic drug that actively increases BMD is PTH preparations. PTH preparation is regarded as one of the most effective treatments for osteoporosis (Non-Patent Document 2); however, since it is a peptide, it needs to be administered by an invasive method. Therefore, there is an expectation for production of a pharmaceutical agent that has PTH-like effects and which can be administered non-invasively.
Hypoparathyroidism is a metabolic disease that exhibits hypocalcemia and hyperphosphatemia caused by insufficiency of PTH secreted from the parathyroid gland, and a variety of associated symptoms. Active vitamin D preparations and Ca agents are being used for the treatment of hypoparathyroidism; however, since the PTH-mediated regulatory mechanism does not work, a sufficient therapeutic effect is not obtained. Furthermore, since active vitamin D formulations enhance urinary Ca excretion, long-term therapy suggests an increased risk of nephropathy. In order to solve these problems, there is an ongoing investigation of replacement therapy that uses PTH preparations against this disease; and an attempt was made to carry out several invasive administrations per day or a continuous administration using a pump to obtain sufficient efficacy (Non-Patent Document 3). Therefore, for hypoparathyroidism treatment, generation of a pharmaceutical agent that has PTH-like effects and which can also be administered non-invasively is desirable.
Also, a pharmaceutical agent having PTH-like effects that can also be administered non-invasively is desired for treatment of diseases such as fracture, adynamic bone disease, achondroplasia, hypochondroplasia, osteomalacia, osteoarthritis, arthritis, thrombocytopenia, hyperphosphatemia, and tumoral calcinosis.
Under such circumstances, the present inventors submitted a patent application in advance based on their discovery that the compound represented by formula (A):
[Patent Document 1 may be referred to for W, X, Y, m, n, R1, R2, R33, and R34 in the formula] and pharmacologically acceptable salts thereof are useful as compounds having PTH-like effects, or more preferably, as a PTH1R agonist, and are useful for prevention and/or treatment of osteoporosis, fracture, osteomalacia, arthritis, thrombocytopenia, hypoparathyroidism, hyperphosphatemia, or tumoral calcinosis, or stem cell mobilization (Patent Document 1).
To produce pharmaceutical agents that have high clinical value and can be administered invasively, it is necessary to consider the in vivo kinetics such as absorption, distribution, metabolism, and excretion of the drug in addition to its direct actions on the target. To enable oral administration in particular, it is desirable to have a pharmaceutical agent having PTH-like effects which are high metabolic stability against human liver microsomes and strong human PTH1R-mediated ability of producing cAMP.
To provide a pharmaceutical agent that can be administered orally to humans, generally a method of confirming the effects of oral administration by in vivo testing that involves use of a model animal. For example, a thyroparathyroidectomized (TPTX) rat is known as an animal model for hypoparathyroidism. To find a therapeutic agent that has strong PTH-like effects and high metabolic stability, and works against hypoparathyroidism when administered orally, it is effective to use a method of finding a compound that acts on rat PTH1R and is stable to the rat's metabolic enzymes, and then examining its actions when orally administered to a TPTX rat model.
In current therapy for hypoparathyroidism, the therapeutic target range for serum Ca concentration is set to a slightly lower range than the lower limit of the normal range at 7.6 to 8.8 mg/dL (Non-Patent Document 4). Since the normal range for rat serum Ca concentration is the same level as for humans at 10 mg/dL or so, to verify the therapeutic effect, it is important to attain a serum Ca concentration in the rat model of the disease within the range from the therapeutic target range in humans (7.6-8.8 mg/dL) to the lower limit for hypercalcemia in humans (approximately 11.2 mg/dL).